Notably, we found that the common G allele of the IL 6 pro moter variant showed association with poor sur vival of patients with advanced gastric cancer treated with palliative chemotherapy. The minor IL 6R C allele showed a weaker selleck chemicals prognostic role than the IL 6 promoter variant. However, in support of a dynamic modulation of the IL 6/sIL 6R system, we observed a possible additive ef fect with worst survival outcomes in the presence of both IL 6 and IL 6R unfavorable genotypes. The different distribution of patients with and without liver metastasis according to the sIL 6R genotypes would also support the role of the IL 6/IL 6R system in the ac quisition of a specific pattern of metastatic spread. In experimental and in vivo models, IL 6 increases the metastatic potential of circulating tumor cells and mod ulates tissue homeostasis in a target organ of metastasis such as the liver.

Also, sIL 6R mediated trans signaling displays pro invasive and pro metastatic signals. It is maximized in rs8192284 IL 6R minor allele carriers and it is likely to promote hematogenous spread, causing a specific pattern of metastatic disease. The common G allele of the rs1800795 IL 6 promoter variant showed association with unfavorable survival out comes of patients with ovarian cancer, breast cancer, neuroblastoma and hematologic malignancies. To the best of our knowledge, there is only one pub lished study reporting the results of a prognostic analysis of IL 6 polymorphisms in gastric cancer patients.

Liao et al showed a significant association between high IL 6 circulating levels and poor survival of stage II III, sur gically resected patients, but the rs1800796 IL 6 variant did not show prognostic role. Notably, they could not in vestigate the IL 6 rs1800795 because of the rarity of the variant allele in Asiatic populations, while the func tional effects of the IL 6 rs1800796 are less extensively studied compared with the IL 6 rs1800795. Less information is available on the clinical impact of the rs8192284 IL 6R genetic variant. In multiple myeloma patients the minor rs8192284 C allele showed association with lower overall survival, but in neuroblastoma Table 2 Results of the multivariate cox proportional to explain different sensitivity and clinical outcomes of patients treated with novel target therapies.

At the same time, IL 6/IL 6R analyses could offer the opportunity of developing an alternative therapeutic strategy. In pa tients with metastatic renal cell cancer, high IL 6 serum levels were predictive of improved progression free sur vival from the multi kinase inhibitor Pazopanib com pared with placebo. In experimental models, IL 6 showed induction of cancer stem cells and epithelial mesenchimal transition phenotype, which are possible condition for resistance to the anti HER 2 compounds trastuzumab and lapatinib. High IL 6 levels showed association with toxicity from Vorinostat in prostate cancer GSK-3 patients.